Despite tremendous progress in our understanding of the primary sensory neurons and spinal cord interneuronal circuits that respond to and transmit pain and itch-provoking stimuli, how these stimuli are interpreted by the brain to produce the perceptions of pain and itch are still unclear. To a great extent, this gap in our knowledge reflects the much more limited information that we have about the projection neurons that carry the information from the spinal cord to the brain. That gap is critical as it is the signals carried by the projection neurons that are ?read? by the brain and that ultimately lead to a perception of pain or itch, and to their various submodalities (heat, cold, mechanical, etc.). Our research program is multidisciplinary, using novel viral, genetic and functional (electrophysiological, behavioral and imaging) approaches to characterize the properties of the projection neurons, the circuits that engage them, their supraspinal targets and the functional consequence of their activity. An important focus of the research program is on the question of convergence or segregation of the circuits that respond to painful or itch-provoking stimuli and the extent to which these circuits are altered in the setting of injury. Our program includes several highly innovative experiments that for the first time will not only determine the molecular heterogeneity of the projection neurons, but will also examine the responses of populations of neurons in the brain to activity in the projection neurons. Defining molecular subtypes of projection neurons and the development of Cre-expressing mice based on these molecular features will permit a host of experiments, including viral-based retrograde (rabies) and anterograde (HSV) tracing of circuits that influence subsets of projection neurons, as well as the behavioral consequence of selective ablation, or DREADD-mediated activation/inhibition of these neurons. Finally, using incredibly powerful Ca2+ imaging techniques that signal the activity of populations of neurons in awake, freely moving mice, we will obtain new information on the behavioral correlates of algogen and pruritogen-evoked supraspinal activity. Using novel behavioral paradigms our program will also provide important insights into the processes through which noxious, and even innocuous stimuli (in the setting of injury), are interpreted as painful. These new approaches will provide information about the quality of the pain that the animal experiences and also offer a powerful validation of the mouse models of chronic pain and itch and their translatability to the human condition.